BESPONSA™ Adverse Reactions

(inotuzumab ozogamicin)

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

•: Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
•: Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
•: Myelosuppression [see Warnings and Precautions (5.3)]
•: Infusion related reactions [see Warnings and Precautions (5.4)]
•: QT interval prolongation [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory B-cell Precursor ALL

Adult Patients

The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [see Clinical Studies (14)].

Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.

In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient.

In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Adverse Reactions With ≥ 10% Incidence* in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System Adverse Reaction	BESPONSA (N=164)		FLAG, MXN/Ara-C, or HIDAC (N=143†)
	All Grades	≥ Grade 3	All Grades	≥ Grade 3
	%	%	%	%
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT). Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. Severity grade of adverse reactions were according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included. † 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ‡ Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. § Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. ¶ Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. # Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. Þ Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. ß Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. à Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. è Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. ð Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. ø Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. ý Fatigue includes the following reported preferred terms: Asthenia and Fatigue. £ Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.
Infections
Infection‡	48	28	76	54
Blood and lymphatic system disorders
Thrombocytopenia§	51	42	61	59
Neutropenia¶	49	48	45	43
Anemia#	36	24	59	47
LeukopeniaÞ	35	33	43	42
Febrile neutropenia	26	26	53	53
Lymphopeniaß	18	16	27	26
Metabolism and nutrition disorders
Decreased appetite	12	1	13	2
Nervous system disorders
Headacheà	28	2	27	1
Vascular disorders
Hemorrhageè	33	5	28	5
Gastrointestinal disorders
Nausea	31	2	46	0
Abdominal painð	23	3	23	1
Diarrhea	17	1	38	1
Constipation	16	0	24	0
Vomiting	15	1	24	0
Stomatitisø	13	2	26	3
Hepatobiliary disorders
Hyperbilirubinemia	21	5	17	6
General disorders and administration site conditions
Fatigueý	35	5	25	3
Pyrexia	32	3	42	6
Chills	11	0	11	0
Investigations
Transaminases increased£	26	7	13	5
Gamma-glutamyltransferase increased	21	10	8	4
Alkaline phosphatase increased	13	2	7	0

Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).

Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
		BESPONSA			FLAG, MXN/Ara-C, or HIDAC
		All Grades	Grade 3/4		All Grades	Grade 3/4
Laboratory Abnormality*	N	%	%	N	%	%
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
Hematology
Platelet count decreased	161	98	76	142	100	99
Hemoglobin decreased	161	94	40	142	100	70
Leukocytes decreased	161	95	82	142	99	98
Neutrophil count decreased	160	94	86	130	93	88
Lymphocytes (absolute) decreased	160	93	71	127	97	91
Chemistry
GGT increased	148	67	18	111	68	17
AST increased	160	71	4	134	38	4
ALP increased	158	57	1	133	52	3
ALT increased	161	49	4	137	46	4
Blood bilirubin increased	161	36	5	138	35	6
Lipase increased	139	32	13	90	20	2
Hyperuricemia	158	16	3	122	11	0
Amylase increased	143	15	2	102	9	1

Pediatric Patients

The safety of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL was evaluated in a multicenter, single-arm, open-label study (ITCC-059) [see Clinical Studies (14)]. Patients (n=53) received the recommended dosage of BESPONSA [see Dosage and Administration (2.1)] or BESPONSA at an initial dose of 1.4 mg/m2/cycle (approximately 0.78 times the recommended initial dosage). Patients received BESPONSA for a median of 2 (range: 1-4) cycles. The median age of patients who received BESPONSA was 9 years (range: 1-17), with 68% male.

Serious adverse reactions occurred in 62% of patients who received BESPONSA. Serious adverse reactions in > 2% of patients included infection (21%), febrile neutropenia (17%), VOD (15%), hemorrhage (4%), pyrexia (6%) and multiorgan failure (2%). Fatal adverse reactions occurred in 8% of patients who received BESPONSA, including multiorgan failure, lung infection, sepsis, and encephalopathy.

Permanent discontinuation of BESPONSA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of BESPONSA in 2 or more patients included ALT increased and platelet count decreased.

Dosage interruptions of BESPONSA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption of BESPONSA in 6 patients included increased transaminases, febrile neutropenia, and headache.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.

Table 9 summarizes the adverse reactions in ITCC-059.

Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)
Severity grade of adverse reactions were according to NCI CTCAE version 4.03.
* Includes other related terms. † Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. ‡ Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage. § Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.
Body System Adverse Reaction	BESPONSA Monotherapy (N=53)
	All Grades	≥ Grade 3
	%	%
General disorders and administration site conditions
Pyrexia	49	4
Edema*	19	0
Fatigue*	17	0
Pain	15	2
Chills	8	0
Blood and lymphatic system disorders
Anemia*	45	38
Febrile neutropenia	28	28
Gastrointestinal disorders
Vomiting	45	2
Nausea	32	0
Abdominal pain*	25	2
Constipation	19	2
Stomatitis*	17	6
Diarrhea	11	0
Infections and infestations
Infection†	43	23
Vascular disorders
Hemorrhage‡	42	6
Hypotension	6	4
Nervous system disorders
Headache*	21	0
Skin and subcutaneous tissue disorders
Rash*	19	4
Pruritis	9	0
Hyperhidrosis	6	0
Musculoskeletal and connective tissue disorders
Pain in extremity	19	2
Back pain	6	0
Neck pain	6	0
Muscular weakness	6	0
Respiratory, thoracic and mediastinal disorders
Cough	17	0
Dyspnea	8	2
Hypoxia	8	4
Hepatobiliary disorders
Veno-occlusive disease*	15	13
Hyperbilirubinemia*	9	8
Metabolism and nutrition disorders
Decreased appetite	11	4
Tumor lysis syndrome	11	11
Investigations
Weight increased	8	2
Injury, poisoning and procedural complications
Infusion related reaction§	8	0
Cardiac disorders
Sinus tachycardia	6	2
Psychiatric disorders
Anxiety	6	0

Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059).

Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059)
Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03.
Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
Laboratory Abnormality		BESPONSA Monotherapy
		All Grades	Grade 3/4
	N	%	%
Hematology
Platelet count decreased	53	100	85
Neutrophil count decreased	53	98	96
White blood cell decreased	53	98	89
Hemoglobin decreased	53	96	42
Lymphocyte count decreased	52	87	73
Chemistry
AST increased	53	87	21
ALT increased	53	83	21
GGT increased	33	79	27
Blood bilirubin increased	53	30	9
ALP increased	53	28	0
Lipase increased	48	23	4
Serum amylase increased	49	14	0

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Adverse Reactions

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

•: Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
•: Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
•: Myelosuppression [see Warnings and Precautions (5.3)]
•: Infusion related reactions [see Warnings and Precautions (5.4)]
•: QT interval prolongation [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Relapsed or Refractory B-cell Precursor ALL

Adult Patients

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Adverse Reactions With ≥ 10% Incidence* in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System Adverse Reaction	BESPONSA (N=164)		FLAG, MXN/Ara-C, or HIDAC (N=143†)
	All Grades	≥ Grade 3	All Grades	≥ Grade 3
	%	%	%	%
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT). Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. Severity grade of adverse reactions were according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included. † 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ‡ Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. § Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. ¶ Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. # Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. Þ Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. ß Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. à Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. è Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. ð Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. ø Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. ý Fatigue includes the following reported preferred terms: Asthenia and Fatigue. £ Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.
Infections
Infection‡	48	28	76	54
Blood and lymphatic system disorders
Thrombocytopenia§	51	42	61	59
Neutropenia¶	49	48	45	43
Anemia#	36	24	59	47
LeukopeniaÞ	35	33	43	42
Febrile neutropenia	26	26	53	53
Lymphopeniaß	18	16	27	26
Metabolism and nutrition disorders
Decreased appetite	12	1	13	2
Nervous system disorders
Headacheà	28	2	27	1
Vascular disorders
Hemorrhageè	33	5	28	5
Gastrointestinal disorders
Nausea	31	2	46	0
Abdominal painð	23	3	23	1
Diarrhea	17	1	38	1
Constipation	16	0	24	0
Vomiting	15	1	24	0
Stomatitisø	13	2	26	3
Hepatobiliary disorders
Hyperbilirubinemia	21	5	17	6
General disorders and administration site conditions
Fatigueý	35	5	25	3
Pyrexia	32	3	42	6
Chills	11	0	11	0
Investigations
Transaminases increased£	26	7	13	5
Gamma-glutamyltransferase increased	21	10	8	4
Alkaline phosphatase increased	13	2	7	0

Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
		BESPONSA			FLAG, MXN/Ara-C, or HIDAC
		All Grades	Grade 3/4		All Grades	Grade 3/4
Laboratory Abnormality*	N	%	%	N	%	%
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
Hematology
Platelet count decreased	161	98	76	142	100	99
Hemoglobin decreased	161	94	40	142	100	70
Leukocytes decreased	161	95	82	142	99	98
Neutrophil count decreased	160	94	86	130	93	88
Lymphocytes (absolute) decreased	160	93	71	127	97	91
Chemistry
GGT increased	148	67	18	111	68	17
AST increased	160	71	4	134	38	4
ALP increased	158	57	1	133	52	3
ALT increased	161	49	4	137	46	4
Blood bilirubin increased	161	36	5	138	35	6
Lipase increased	139	32	13	90	20	2
Hyperuricemia	158	16	3	122	11	0
Amylase increased	143	15	2	102	9	1

Pediatric Patients

Table 9 summarizes the adverse reactions in ITCC-059.

Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)
Severity grade of adverse reactions were according to NCI CTCAE version 4.03.
* Includes other related terms. † Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. ‡ Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage. § Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.
Body System Adverse Reaction	BESPONSA Monotherapy (N=53)
	All Grades	≥ Grade 3
	%	%
General disorders and administration site conditions
Pyrexia	49	4
Edema*	19	0
Fatigue*	17	0
Pain	15	2
Chills	8	0
Blood and lymphatic system disorders
Anemia*	45	38
Febrile neutropenia	28	28
Gastrointestinal disorders
Vomiting	45	2
Nausea	32	0
Abdominal pain*	25	2
Constipation	19	2
Stomatitis*	17	6
Diarrhea	11	0
Infections and infestations
Infection†	43	23
Vascular disorders
Hemorrhage‡	42	6
Hypotension	6	4
Nervous system disorders
Headache*	21	0
Skin and subcutaneous tissue disorders
Rash*	19	4
Pruritis	9	0
Hyperhidrosis	6	0
Musculoskeletal and connective tissue disorders
Pain in extremity	19	2
Back pain	6	0
Neck pain	6	0
Muscular weakness	6	0
Respiratory, thoracic and mediastinal disorders
Cough	17	0
Dyspnea	8	2
Hypoxia	8	4
Hepatobiliary disorders
Veno-occlusive disease*	15	13
Hyperbilirubinemia*	9	8
Metabolism and nutrition disorders
Decreased appetite	11	4
Tumor lysis syndrome	11	11
Investigations
Weight increased	8	2
Injury, poisoning and procedural complications
Infusion related reaction§	8	0
Cardiac disorders
Sinus tachycardia	6	2
Psychiatric disorders
Anxiety	6	0

Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059).

Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059)
Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03.
Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
Laboratory Abnormality		BESPONSA Monotherapy
		All Grades	Grade 3/4
	N	%	%
Hematology
Platelet count decreased	53	100	85
Neutrophil count decreased	53	98	96
White blood cell decreased	53	98	89
Hemoglobin decreased	53	96	42
Lymphocyte count decreased	52	87	73
Chemistry
AST increased	53	87	21
ALT increased	53	83	21
GGT increased	33	79	27
Blood bilirubin increased	53	30	9
ALP increased	53	28	0
Lipase increased	48	23	4
Serum amylase increased	49	14	0

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Adverse Reactions

6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

•: Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
•: Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
•: Myelosuppression [see Warnings and Precautions (5.3)]
•: Infusion related reactions [see Warnings and Precautions (5.4)]
•: QT interval prolongation [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Relapsed or Refractory B-cell Precursor ALL

Adult Patients

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].

Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 7. Adverse Reactions With ≥ 10% Incidence* in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
Body System Adverse Reaction	BESPONSA (N=164)		FLAG, MXN/Ara-C, or HIDAC (N=143†)
	All Grades	≥ Grade 3	All Grades	≥ Grade 3
	%	%	%	%
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT). Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. Severity grade of adverse reactions were according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included. † 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ‡ Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. § Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. ¶ Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. # Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. Þ Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. ß Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. à Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. è Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. ð Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. ø Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. ý Fatigue includes the following reported preferred terms: Asthenia and Fatigue. £ Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.
Infections
Infection‡	48	28	76	54
Blood and lymphatic system disorders
Thrombocytopenia§	51	42	61	59
Neutropenia¶	49	48	45	43
Anemia#	36	24	59	47
LeukopeniaÞ	35	33	43	42
Febrile neutropenia	26	26	53	53
Lymphopeniaß	18	16	27	26
Metabolism and nutrition disorders
Decreased appetite	12	1	13	2
Nervous system disorders
Headacheà	28	2	27	1
Vascular disorders
Hemorrhageè	33	5	28	5
Gastrointestinal disorders
Nausea	31	2	46	0
Abdominal painð	23	3	23	1
Diarrhea	17	1	38	1
Constipation	16	0	24	0
Vomiting	15	1	24	0
Stomatitisø	13	2	26	3
Hepatobiliary disorders
Hyperbilirubinemia	21	5	17	6
General disorders and administration site conditions
Fatigueý	35	5	25	3
Pyrexia	32	3	42	6
Chills	11	0	11	0
Investigations
Transaminases increased£	26	7	13	5
Gamma-glutamyltransferase increased	21	10	8	4
Alkaline phosphatase increased	13	2	7	0

Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
		BESPONSA			FLAG, MXN/Ara-C, or HIDAC
		All Grades	Grade 3/4		All Grades	Grade 3/4
Laboratory Abnormality*	N	%	%	N	%	%
Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
* Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
Hematology
Platelet count decreased	161	98	76	142	100	99
Hemoglobin decreased	161	94	40	142	100	70
Leukocytes decreased	161	95	82	142	99	98
Neutrophil count decreased	160	94	86	130	93	88
Lymphocytes (absolute) decreased	160	93	71	127	97	91
Chemistry
GGT increased	148	67	18	111	68	17
AST increased	160	71	4	134	38	4
ALP increased	158	57	1	133	52	3
ALT increased	161	49	4	137	46	4
Blood bilirubin increased	161	36	5	138	35	6
Lipase increased	139	32	13	90	20	2
Hyperuricemia	158	16	3	122	11	0
Amylase increased	143	15	2	102	9	1

Pediatric Patients

Table 9 summarizes the adverse reactions in ITCC-059.

Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)
Severity grade of adverse reactions were according to NCI CTCAE version 4.03.
* Includes other related terms. † Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. ‡ Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage. § Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.
Body System Adverse Reaction	BESPONSA Monotherapy (N=53)
	All Grades	≥ Grade 3
	%	%
General disorders and administration site conditions
Pyrexia	49	4
Edema*	19	0
Fatigue*	17	0
Pain	15	2
Chills	8	0
Blood and lymphatic system disorders
Anemia*	45	38
Febrile neutropenia	28	28
Gastrointestinal disorders
Vomiting	45	2
Nausea	32	0
Abdominal pain*	25	2
Constipation	19	2
Stomatitis*	17	6
Diarrhea	11	0
Infections and infestations
Infection†	43	23
Vascular disorders
Hemorrhage‡	42	6
Hypotension	6	4
Nervous system disorders
Headache*	21	0
Skin and subcutaneous tissue disorders
Rash*	19	4
Pruritis	9	0
Hyperhidrosis	6	0
Musculoskeletal and connective tissue disorders
Pain in extremity	19	2
Back pain	6	0
Neck pain	6	0
Muscular weakness	6	0
Respiratory, thoracic and mediastinal disorders
Cough	17	0
Dyspnea	8	2
Hypoxia	8	4
Hepatobiliary disorders
Veno-occlusive disease*	15	13
Hyperbilirubinemia*	9	8
Metabolism and nutrition disorders
Decreased appetite	11	4
Tumor lysis syndrome	11	11
Investigations
Weight increased	8	2
Injury, poisoning and procedural complications
Infusion related reaction§	8	0
Cardiac disorders
Sinus tachycardia	6	2
Psychiatric disorders
Anxiety	6	0

Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059).

Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059)
Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03.
Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
Laboratory Abnormality		BESPONSA Monotherapy
		All Grades	Grade 3/4
	N	%	%
Hematology
Platelet count decreased	53	100	85
Neutrophil count decreased	53	98	96
White blood cell decreased	53	98	89
Hemoglobin decreased	53	96	42
Lymphocyte count decreased	52	87	73
Chemistry
AST increased	53	87	21
ALT increased	53	83	21
GGT increased	33	79	27
Blood bilirubin increased	53	30	9
ALP increased	53	28	0
Lipase increased	48	23	4
Serum amylase increased	49	14	0

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